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3rew
From Proteopedia
Crystal structure of an lmp2a-derived peptide bound to human class i mhc hla-a2
Structural highlights
Disease[B2MG_HUMAN] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:241600]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.[1] Note=Beta-2-microglobulin may adopt the fibrillar configuration of amyloid in certain pathologic states. The capacity to assemble into amyloid fibrils is concentration dependent. Persistently high beta(2)-microglobulin serum levels lead to amyloidosis in patients on long-term hemodialysis.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Function[1A02_HUMAN] Involved in the presentation of foreign antigens to the immune system. [LMP2_EBVB9] Isoform LMP2A maintains EBV latent infection of B-lymphocyte, by preventing lytic reactivation of the virus in response to surface immunoglobulin (sIg) cross-linking. Acts like a dominant negative inhibitor of the sIg-associated protein tyrosine kinases, LYN and SYK. Also blocks translocation of the B-cell antigen receptor (BCR) into lipid rafts, preventing the subsequent signaling and accelerated internalization of the BCR upon BCR cross-linking. Serves as a molecular scaffold to recruit SYK, LYN and E3 protein-ubiquitin ligases, such as ITCH and NEDD4L, leading to ubiquitination and potential degradation of both tyrosines kinases. Possesses a constitutive signaling activity in non-transformed cells, inducing bypass of normal B lymphocyte developmental checkpoints allowing immunoglobulin-negative cells to colonize peripheral lymphoid organs.[15] [16] Isoform LMP2B may be a negative regulator of isoform LMP2A.[17] [18] [B2MG_HUMAN] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system. Publication Abstract from PubMedImmunotherapies targeting peptides presented by allogeneic MHC molecules offer the prospect of circumventing tolerance to key tumor-associated self-antigens. However, the degree of antigen specificity mediated by alloreactive T cells, and their ability to discriminate normal tissues from transformed cells presenting elevated antigen levels, is poorly understood. We examined allorecognition of an HLA-A2-restricted Hodgkin's lymphoma-associated antigen and were able to isolate functionally antigen-specific allo-HLA-A2-restricted T cells from multiple donors. Binding and structural studies, focused on a prototypic allo-HLA-A2-restricted T-cell receptor (TCR) termed NB20 derived from an HLA-A3 homozygote, suggested highly peptide-specific allorecognition that was energetically focused on antigen, involving direct recognition of a distinct allopeptide presented within a conserved MHC recognition surface. Although NB20/HLA-A2 affinity was unremarkable, TCR/MHC complexes were very short-lived, consistent with suboptimal TCR triggering and tolerance to low antigen levels. These data provide strong molecular evidence that within the functionally heterogeneous alloreactive repertoire, there is the potential for highly antigen-specific "allo-MHC-restricted" recognition and suggest a kinetic mechanism whereby allo-MHC-restricted T cells may discriminate normal from transformed tissue, thereby outlining a suitable basis for broad-based therapeutic targeting of tolerizing tumor antigens. Structural and energetic evidence for highly peptide-specific tumor antigen targeting via allo-MHC restriction.,Simpson AA, Mohammed F, Salim M, Tranter A, Rickinson AB, Stauss HJ, Moss PA, Steven NM, Willcox BE Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21176-81. Epub 2011 Dec 12. PMID:22160697[19] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Large Structures | Mohammed, F | Moss, P A.H | Rickinson, A B | Salim, M | Stauss, H J | Steven, N M | Tranter, A | Willcox, B E | Wood, A | Alloreactivity | Epstein barr virus | Glycoprotein | Hla-a2 | Immune response | Immune system | Immunoglobulin domain | Mhc class i | Mhc i | Tumour antigen targeting
